Spatially Resolved Bioenergetic and Genetic Reprogramming Through the Brain of Rats Bearing Implanted C6 Gliomas As Detected by Multinuclear High-Resolution Magic Angle Spinning and Genomic Analysis

• Published in: Journal of proteome research Vol. 17; no. 9; pp. 2953 - 2962
• Main Authors: Righi, Valeria, García-Martín, María-Luisa, Mucci, Adele, Schenetti, Luisa, Tugnoli, Vitaliano, Lopez-Larrubia, Pilar, Cerdán, Sebastián
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 07.09.2018
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biopsy; Brain Neoplasms - diagnostic imaging; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Carbon Isotopes; Caudate Nucleus - diagnostic imaging; Caudate Nucleus - metabolism; Caudate Nucleus - pathology; Cellular Reprogramming; Female; Gene Expression Profiling; Gene Expression Regulation; Glioma - diagnostic imaging; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glucose - metabolism; Glutamic Acid - metabolism; Glycolysis - genetics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Lactic Acid - metabolism; Magnetic Resonance Imaging - methods; Neoplasm Transplantation; Oxidative Phosphorylation; Rats; Rats, Wistar; Transcription Factors - genetics; Transcription Factors - metabolism; Transplantation, Heterologous; HRMAS; genetic reprogramming; genomics; C6 glioma; metabolomics; metabolic reprogramming
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/acs.jproteome.8b00130

We used 1H, 13C HRMAS and genomic analysis to investigate regionally the transition from oxidative to glycolytic phenotype and its relationship with altered gene expression in adjacent biopsies through the brain of rats bearing C6 gliomas. Tumor-bearing animals were anesthetized and infused with a solution of [1-13C]-glucose, and small adjacent biopsies were obtained spanning transversally from the contralateral hemisphere (regions I and II), the right and left peritumoral areas (regions III and V, respectively), and the tumor core (region IV). These biopsies were analyzed by 1H, 13C HRMAS and by quantitative gene expression techniques. Glycolytic metabolism, as reflected by the [3-13C]-lactate content, increased clearly from regions I to IV, recovering partially to physiological levels in region V. In contrast, oxidative metabolism, as reflected by the [4-13C]-glutamate labeling, decreased in regions I–IV, recovering partially in region V. This metabolic shift from normal to malignant metabolic phenotype paralleled changes in the expression of HIF1α, HIF2α, HIF3α genes, downstream transporters, and regulatory glycolytic, oxidative, and anaplerotic genes in the same regions. Together, our results indicate that genetic and metabolic alterations occurring in the brain of rats bearing C6 gliomas colocalize in situ and the profile of genetic alterations in every region can be inferred from the metabolomic profiles observed in situ by multinuclear HRMAS.